Project Summary/Abstract The primary long-term goal of this project is to elucidate the nature of the underlying neural mechanisms responsible for the reinforcing and motivational properties of stimulant and opiate drugs of abuse. Behavioral, pharmacological, physiological and neurochemical methodologies will be combined to address two specific aims each of which builds upon and extends the findings obtained during the first nineteen years of the project. Specific Aim 1 is to continue ongoing investigations into the neurobiology of cocaine[unreadable]s mixed rewarding and anxiogenic properties with the goal of better understanding the brain loci and neurochemical bases of the drug[unreadable]s dual and opposing actions. Specific Aim 2 is to distinguish underlying motivational processes that serve to initiate drug-seeking behavior from those reinforcing processes that are activated as a consequence of drug self-administration. The primary behavioral method to be employed in the proposed research is a novel model of drug-seeking in which animals traverse a straight alley once a day to obtain a single IV injection of a drug reinforcer (e.g., cocaine, nicotine, heroin[unreadable]). In this model, the time required to cross the runway and enter the goal box (i.e. Run Time) provides a valid and reliable index of the undrugged subject[unreadable]s motivation to seek the drug reinforcer. Since animals are tested on but a single trial/day, the resulting behavioral data are always collected prior to drug delivery and hence are devoid of any confounding performance-altering properties of the drug reinforcer itself. The runway method is also uniquely sensitive to concurrent positive and negative properties of goal-box events. Ss exhibit an oscillating approach-avoidance conflict (i.e., retreat behaviors) about entering the goal box for drugs having mixed positive+negative features (e.g., cocaine). These behavioral measures of drug-seeking motivation will be combined with physiological measures of arousal (radio-telemetric assessments of heart rate and respiration), and neurochemical indices of drug-induced changes in brain function (c-Fos, in vivo microdialysis). Experiments are planned to employ intracranial and IV self-administration of reinforcing drugs, to challenge such self-administration with systemic and centrally applied selective agonists and/or antagonists of neurotransmitter function (e.g., DA, 5-HT, CRF), and to assess the impact of lidocaine-induced reversible lesions of selective brain structures on the reinforcing and motivating properties of self-administered drugs. Together, these studies are intended to provide important new information on the complex neurobiological and neurobehavioral factors responsible for the self-administration of cocaine and other drugs of abuse, and to further test the hypothesis that different/dissociable neural systems are responsible for the motivational antecedents of drug abuse (drug seeking) and the reinforcing consequences of actually attaining the drug (drug administration).